Formal synthesis of (±)-pancracine using stereoselective radical cyclization of N-(2-cyclohexenyl)-α-aryl-α-(phenylthio)acetamide

Article abstract of DOI:10.1055/s-1998-1937

(Me₃Si)₃SiH-mediated 5-exo-trig radical cyclization of N-(2-cyclohexcnyl)-α-aryl-α-(phenylthio)acetamide 19 proceeded in a stereoselective manner to give (3R*,3aS*,7aS*)-3-aryloctahydroindol-2-one 20. The product was transformed into the key intermediate 25 for the synthesis of (±)-pancracine (1), a montanine-type Amaryllidaceae alkaloid.

Full text of DOI:10.1055/s-1998-1937

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Formal Synthesis of (±)-Pancracine Using Stereoselective Radical Cyclization of
N-(2-Cyclohexenyl)-α-aryl-α-(phenylthio)acetamide
Masazumi Ikeda,*a Masahiro Hamada,a Takashi Yamashita,a Fumi Ikegami,a Tatsunori Sato,a Hiroyuki Ishibashi*b
a Kyoto Pharmaceutical University, Misasagi, Yamashina, Kyoto 607-8414, Japan
b Faculty of Pharmaceutical Sciences, Kanazawa University, Takara-machi, Kanazawa 920-0934, Japan
Fax +81(75)595-4763; E-mail: ikeda@mb.kyoto-phu.ac.jp
Received 3 September 1998
Abstract: (Me3Si)3SiH-mediated 5-exo-trig radical cyclization of N-(2-
O
cyclohexenyl)-α-aryl-α-(phenylthio)acetamide 19 proceeded in
a
O
stereoselective manner to give (3R*,3aS*,7aS*)-3-aryloctahydroindol-
2-one 20. The product was transformed into the key intermediate 25 for
the synthesis of (±)-pancracine (1), a montanine-type Amaryllidaceae
alkaloid.
a
b
O
O
N
O
O
PMB
6
7
The 5,11-methanomorphanthridine skeleton is a basic structural element
of montanine-type Amaryllidaceae alkaloids such as pancracine (1) and
montanine (2).1 The first total synthesis of this class of alkaloids were
reported concurrently by Overman [for (±)-pancracine]2 and Hoshino
[for (±)-pancracine and (±)-montanine]3 in 1991, and subsequently
many works have been reported for the synthesis of optically active and
racemic methanomorphanthridine family of Amaryllidaceae alkaloids.4
In continuation of our studies directed towards the synthesis of natural
products using radical cyclizations as the key step,5 we were interested
in the synthesis of 3-aryloctahydroindole 3 through 5-endo-trig6 or 5-
exo-trig7 cyclization of the N-(1- or 2-cyclohexenyl)carbamoylmethyl
radical 4 or 5. The Pictet-Spengler cyclization of the compounds having
O
O
O
O
O
O
c
O
PhSe
O
O
N
N
PMB
8 (77% from 6)
PMB
9 (65%)
PMB = p-methoxybenzyl
Scheme 2. (a) p-methoxybenzylamine, benzene, reflux; (b) (3,4-methylene-
dioxyphenyl)acetic pivalic anhydride, pyridine, benzene, 30-40 °C; (c) LDA,
HMPA, THF, -78 °C then PhSeCl.
the same stereochemistry as
3
is known to provide the
methanomorphanthridines.2 We found that the 5-exo-trig cyclization of
N-(2-cyclohexenyl)-α-aryl-α-(phenylthio)acetamide 19 proceeded in a
stereoselective manner to give (3R*,3aS*,7aS*)-3-aryloctahydroindol-
2-one 20. The present paper describes an application of the method to
the formal synthesis of (±)-pancracine.
spectroscopy) was obtained in 82% combined yield. The structures of
10a and 10b were confirmed by the following chemical evidence.
Hydrolysis of the mixture of ethylene acetals 10a,b gave ketones 11a
and 11b in 54 and 47% isolated yields, respectively, and each of the
ketones 11a and 11b was again protected with ethylene glycol to give
acetals 10a (mp 148-150 °C) and 10b (an oil) as single stereoisomers,
respectively. Compounds 10a and 10b were then heated independently
with EtONa in boiling EtOH or with tert-BuOK in boiling tert-BuOH to
result in the recovery of the starting material in both cases. These results
indicate that two hydrogen atoms between 3- and 3a-positions of both
10a and 10b have the trans relationship.8 The cis-stereochemistry of the
ring struncture of 10a was established by transforming the same
compound prepared by an alternate method to the known compound 25
(vide infra), and hence the stereochemistry of the ring structure of 10b
was deduced to be trans.
O
O
1
OR
O
11
2
3
H
H
H
X
O
OH
Y
4
N5
H
N
H
R = H: Pancracine (1)
R = Me: Montanine (2)
3
X
X
Ar
•
Ar
•
Y
Y
or
Thus, the 5-endo-trig cyclization of the carbamoylmethyl radical 4
resulted in the formation of a considerable amount of the undesired
isomer 10b. Therefore, our attention was next turned to the 5-exo-trig
O
N
O
N
R
R
5
4
cyclization of the carbamoylmethyl radical
aryloctahydroindol-2-ones.
5 leading to 3-
Ar = 3,4-methylenedioxyphenyl
Scheme 1
The radical precursor 19 was prepared as follows. The Friedel-Crafts
reaction of chlorosulfide 139 with 1,2-(methylenedioxy)benzene (12) in
the presence of TiCl4 gave ester 14 (75%), which was hydrolyzed to
give carboxylic acid 15 (quant.). On the other hand, according to the
procedure reported by Bäckvall,10 cis-1-acetoxy-4-chloro-2-
cyclohexene 17, prepared from 1,3-cyclohexadiene (16),11 was treated
We initiated our investigation by examining the 5-endo-trig cyclization
of the carbamoylmethyl radical 4. The synthesis of the radical precursor
9 was begun by condensation of 1,4-cyclohexanedione monoethylene
acetal 6 with p-methoxybenzylamine to give imine 7. Acylation of 7
with (3,4-methylenedioxyphenyl)acetic pivalic anhydride gave enamide
8 (an oil), which was then treated successively with LDA and
phenylselenenyl chloride to give 9 (an oil).
with
p-methoxybenzylamine
in
the
presence
of
bis(dibenzylideneacetone)palladium (0) [Pd(dba)2] to give amine 18 in
81% yield. Compound 18 was acylated with carboxylic acid 15 in the
presence of DCC to give 19 (an oil) in 79% yield.
When a boiling solution of 9 in benzene was treated slowly with a
benzene solution of 1.1 equiv. of tributyltin hydride and a catalytic
quantity of azobis(isobutyronitrile) (AIBN), an inseparable mixture of
two cyclization products 10a and 10b (ca. 1:1 by 1H NMR

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SYNLETT
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from 23. The melting point (125-126 °C, lit.4c 125 °C) and 1H NMR
spectrum of 25 herein obtained was identical with those of an authentic
sample.12 Since compound 25 has already been converted to (±)-
pancracine (1),4c the present sequence of the reactions means in a
formal sense a total synthesis of (±)-pancracine.
H
H
H
H
H
H
O
O
Ar
Ar
a
O
O
+
9
O
N
O
N
(82%)
PMB
PMB
10b
10a
H
H
H
H
c
c
(quant.)
(97%)
H
Ar
OH
Ar
O
a
b
H
H
H
20
Ar
O
Ar
O
b
O
N
O
N
10a,b
+
H
H
PMB
PMB
O
N
O
N
H
H
21 (95%)
11a (99%)
PMB
PMB
11a (54%)
11b (47%)
H
H
O
H
H
O
Ar
Ar
d
c
Ar = 3,4-methylenedioxyphenyl
PMB = p-methoxybenzyl
O
O
O
N
N
R
Scheme 3. (a) Bu3SnH, AIBN, benzene, reflux; (b) 5% HCl, acetone, reflux; (c)
ethylene glycol, TsOH, benzene, reflux.
H
H
PMB
10a (95%)
22: R = PMB (87%)
23: R = Cbz (86%)
e
H
H
O
SPh
O
H
Ar
O
f
O
g
O
O
SPh
O
a
CO2R
+
O
N
H
Cl
CO2Et
13
O
b
N
H
H
ÅEHCl
14: R = Et (75%)
15: R = H (quant.)
12
24
25 (64% from 23)
Ar = 3,4-methylenedioxyphenyl
PMB = p-methoxybenzyl
OAc
OAc
e
c
d
Scheme 5. (a) LiOH-H2O, H2O-MeOH, reflux; (b) DMSO, (COCl)2, NEt3,
CH2Cl2, -60 °C; (c) ethylene glycol, TsOH, benzene, reflux; (d) AlH3
(LiAlH4-AlCl3), THF-Et2O, r.t.; (e) CbzCl, benzene, reflux; (f) H2, Pd-C, conc.
HCl, MeOH, r.t.; (g) (i) 36% formalin, NEt3, MeOH, r.t., (ii) 6 N HCl, MeOH,
30 °C.
Cl
HN
PMB
16
18 (81%)
17 (89%)
O
O
O
O
Thus, we revealed that the 5-exo-trig radical cyclization of N-(2-
H
H
H
SPh
OAc
OAc
cyclohexenyl)-α-aryl-α-(phenylthio)acetamides provided
stereoselective synthesis of (3R*,3aS*,7aS*)-3-arylhydroindoles, which
are useful intermediates for the synthesis of 5,11-
methanomorphanthridine alkaloids.
a
new
f
O
N
O
N
PMB
PMB
19 (79%)
20 (84%)
PMB = p-methoxybenzyl
Acknowledgements: This work was supported by a Grant-in-Aid for
Scientific Research from the Ministry of Education, Science, Sports,
and Culture of Japan.
Scheme 4. (a) TiCl4, CHCl3, 0 °C to r.t.; (b) (i) KOH, H2O-EtOH, reflux, (ii)
HCl; (c) Pd(OAc)2, LiCl, LiOAc-2H2O, p-benzoquinone, AcOH, r.t.; (d)
p-methoxybenzylamine, Pd(dba)2, PPh3, NEt3, THF, r.t.; (e) 15, DCC, DMAP,
CH2Cl2 , r.t.; (f) (Me3Si)3SiH, AIBN, benzene, reflux.
References and Notes
(1) For comprehensive reviews of Amaryllidaceae alkaloids, see:
Martin, S.F. In The Alkaloids; Brossi, A., Ed.; Academic Press:
New York, 1987; Vol. 30, pp 251-376. Hoshino, O. In The
Alkaloids; Cordell, G.A., Ed.; Academic Press: New York, 1998;
Vol. 51, pp 323-424.
When a boiling solution of 19 in benzene was treated slowly with a
mixture of 4 equiv. of tris(trimethylsilyl)silane and a catalytic quantity
of AIBN, (3R*,3aS*,7aS*)-3-aryloctahydroindol-2-one 20 (mp 149-150
°C) was obtained in high yield (84%) as a single stereoisomer.
The stereochemistry of 20 was confirmed by transforming it to the key
intermediate 25 for the synthesis of (±)-pancracine. Thus, hydrolysis of
the acetoxy group of 20 with LiOH followed by Swern oxidation of the
resulting alcohol 21 gave keto-lactam 11a, which was identical to that
obtained by hydrolysis of 10a, one of the radical cyclization products
from 9. Protection of ketone 11a with ethylene glycol followed by
reduction of the resulting lactam 10a with alane gave amine 22 (87%).
Treatment of 22 with benzyloxycarbonyl chloride gave carbamate 23
(an oil) (86%), whose hydrogenolysis in the presence of hydrochloric
acid gave the amine hydrochloride 24. Compound 24 was then subjected
to the Pictet-Spengler cyclization to give, with concomitant deprotection
of the ethylene acetal, 5,11-methanomorphanthridine 25 in 64% yield
(2) Overman, L.E.; Shim, J. J. Org. Chem. 1991, 56, 5005.
(3) Ishizaki, M.; Hoshino, O.; Iitaka, Y. Tetrahedron Lett. 1991, 32,
7079.
(4) (a) Overman, L.E.; Shim, J. J. Org. Chem. 1993, 58, 4662. (b)
Ishizaki, M.; Hoshino, O.; Iitaka, Y. J. Org. Chem. 1992, 57, 7285.
(c) Ishizaki, M.; Kurihara, K.; Tanazawa, E.; Hoshino, O. J.
Chem. Soc., Perkin Trans. 1 1993, 101. (d) Jin, J.; Weinreb, S.M.
J. Am. Chem. Soc. 1997, 119, 2050.
(5) For recent references, see (a) Ishibashi, H.; Kameoka, C.;
Kodama, K.; Kawanami, H.; Hamada, M.; Ikeda, M. Tetrahedron
1997, 53, 9611. (b) Ishibashi, H.; Kawanami, H.; Ikeda, M. J.

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Chem. Soc., Perkin Trans. 1 1997, 817. (c) Ishibashi, H.;
Kawanami, H.; Nakagawa, H.; Ikeda, M. J. Chem. Soc., Perkin
Trans. 1 1997, 2291. (d) Ikeda, M.; Kugo, Y.; Yamazaki, T.; Sato,
T. J. Chem. Soc., Perkin Trans. 1 1997, 3339. (e) Ishibashi, H.;
Higuchi, M.; Ohba, M.; Ikeda, M. Tetrahedron Lett. 1998, 39, 75.
(f) Ikeda, M.; Teranishi, H.; Nozaki, K.; Ishibashi, H. J. Chem.
Soc., Perkin Trans. 1 1998, 1691.
(8) It is known that 3-phenyloctahydroindol-2-one having cis-
stereochemistry of two hydrogen atoms between 3- and 3a-
positions, on treatment with EtONa in boiling EtOH, isomerizes to
the thermodynamically more stable corresponding trans-isomer.
See: ref 6.
(9) Ishibashi, H.; Ikeda, M.; Choi, H.D.; Nakagawa, H.; Ueda, Y.;
Tamura, Y. Chem. Pharm. Bull. 1985, 33, 5310 and references
cited therein.
(6) Sato, T.; Nakamura, N.; Ikeda, K.; Okada, M.; Ishibashi, H.;
Ikeda, M. J. Chem. Soc., Perkin Trans. 1 1992, 2399.
(10) Gatti, R.G.P.; Larsson, A.L.E.; Bäckvall, J.-E. J. Chem. Soc.,
Perkin Trans. 1 1997, 577.
(7) Ishibashi, H.; So, T.S.; Okochi, K.; Sato, T.; Nakamura, N.;
Nakatani, H.; Ikeda, M. J. Org. Chem. 1991, 56, 95. (b) Curran,
D.P.; Tamine, J. J. Org. Chem. 1991, 56, 2746. (c) Ishibashi, H.;
Uemura, N.; Nakatani, H.; Okazaki, M.; Sato, T.; Nakamura, N.;
Ikeda, M. J. Org. Chem. 1993, 58, 2360.
(11) Bäckvall, J.-E.; Nyström, J.-E.; Nordberg, R.E. J. Am. Chem. Soc.
1985, 107, 3676.
(12) The authors thank Professor Hoshino, Science University of
Tokyo, for providing 1H NMR spectrum of 25.